The general goals of this project is to define 1) the role of human retroviruses that are associated with chronic-progressive neurologic disease and 2) the host immune responses to these agents that may be involved in the pathogenesis of these disorders. Over the past year, a number of specific research efforts have been targeted to address these broad issues. They include: 1) the continued definition of CD8+, HTLV-I specific, HLA class-I-restricted cytotoxic T lymphocyte (CTL) from patients with HTLV-I-associated myelopathy-tropical spastic paraparesis (HAM-TSP) and the role these cells play in the pathogenesis of this disorder; 2) the detection of HTLV-I in the central nervous system of HAM-TSP patients by use of in situ hybridization techniques and the development of in situ-polymerase chain reaction to amplify low viral copy number in these tissues; 3) the demonstration of HTLV-I-specific T-cell responses from HTLV-I seronegative individuals at risk for exposure to HTLV-I and; 4) the molecular characterization of human retroviruses isolated from patients with HAM-TSP and other chronic-progressive neurologic diseases. The major findings of these studies are; 1) CD8+, CTL directly isolated from peripheral blood lymphocytes or cerebrospinal fluid of HAM-TSP patients are specific for immunodominant peptides of the tax region of HTLV-I and are restricted to particular HLA alleles; 2) exceptionally high precursor frequencies were demonstrated to these peptides; 3) immunodominant peptides can be used to anergize or delete these cells; 4) HTLV-I tax mRNA signals were detected in spinal cord lesions of HAM-TSP patients; 5) the technique of in situ-PCR was developed and successfully amplified HTLV-I tax DNA from PBL of HAM-TSP patients; 6) HTLV-I responses to synthetic peptides of HTLV-I could be demonstrated from HTLV-I seronegative, PCR negative individuals known to be exposed to this virus; 7) HTLV-I molecular sequences were identified in an HTLV-I seronegative individual with a chronic-progressive neurologic disease; 8) HTLV-II has been unequivocally identified, both molecularly and immunologically, in an individual with a chronic myelopathy indistinguishable from HAM-TSP.